{"doi":"10.17615/7nbp-cm42","title":"Protein Phosphatase 2A Catalytic Subunit α Plays a MyD88-Dependent, Central Role in the Gene-Specific Regulation of Endotoxin Tolerance","abstract":"MyD88, the intracellular adaptor of most TLRs, mediates either pro-inflammatory or immunosuppressive signaling that contributes to chronic inflammation-associated diseases. Although gene-specific chromatin modifications regulate inflammation, the role of MyD88 signaling in establishing such epigenetic landscapes under different inflammatory states remains elusive. Using quantitative proteomics to enumerate the inflammation-phenotypic constituents of MyD88 interactome, we found that in endotoxin-tolerant macrophages PP2Ac enhances its association with MyD88, and is constitutively activated. Knockdown of PP2Ac prevents suppression of pro-inflammatory genes and resistance to apoptosis. Through sitespecific dephosphorylation constitutively active PP2Ac disrupts the signal-promoting TLR4-MyD88 complex, and broadly suppresses the activities of multiple pro-inflammatory/proapoptotic pathways as well, shifting pro-inflammatory MyD88 signaling to a pro-survival mode. Constitutively active PP2Ac translocated with MyD88 into the nuclei of tolerant macrophages establishes the immunosuppressive pattern of chromatin modifications and represses chromatin remodeling to selectively silence pro-inflammatory genes, coordinating the MyD88-dependent inflammation control at both signaling and epigenetic levels under endotoxin-tolerant conditions.","journal":"UNC Libraries","year":2020,"id":138831,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":600919,"name":"Cui Liu","orcid":"0000-0003-2979-2040","position":1,"is_corresponding":false},{"id":57593,"name":"Ling Xie","orcid":"0000-0002-3577-8774","position":2,"is_corresponding":false},{"id":600920,"name":"Jing Yu","orcid":"0000-0001-7752-9971","position":3,"is_corresponding":false},{"id":593564,"name":"Leslie V. Parise","orcid":"0000-0002-6860-4252","position":4,"is_corresponding":false},{"id":11782,"name":"Yanbao Yu","orcid":"0000-0003-2994-1974","position":5,"is_corresponding":false},{"id":599844,"name":"Stephen P. Holly","orcid":"0000-0001-7220-6823","position":6,"is_corresponding":false},{"id":225654,"name":"Jenny P.‐Y. Ting","orcid":"0000-0002-3282-419X","position":7,"is_corresponding":false},{"id":541663,"name":"Ruyun Du","orcid":null,"position":8,"is_corresponding":false},{"id":260532,"name":"Zhen Yan","orcid":"0000-0002-4826-9813","position":9,"is_corresponding":false},{"id":336267,"name":"Li Wang","orcid":"0000-0001-7692-5067","position":10,"is_corresponding":false},{"id":600921,"name":"Penggao Dai","orcid":"0000-0001-6211-4634","position":11,"is_corresponding":false},{"id":11742,"name":"Xian Chen","orcid":"0000-0002-8358-1247","position":12,"is_corresponding":false},{"id":255663,"name":"Yisong Y. Wan","orcid":"0000-0003-4346-9717","position":13,"is_corresponding":false},{"id":11802,"name":"Harsha P. Gunawardena","orcid":"0000-0003-3245-3293","position":14,"is_corresponding":false},{"id":502184,"name":"Debra J. Taxman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:06.651725Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}